The present invention relates to novel compositions of matter. These novel compositions are to be used in the treatment of conditions or symptoms due to certain disease conditions in mammals. In particular this invention relates to novel compounds which are useful in inhibiting the formation of products of the "aracidonic acid cascade" in such pathological states. This inhibition is accomplished by inhibiting the action of the enzyme phospholipase A.sub.2, an important mediator in the cascade, by administering certain novel 4,1-benzoxazepin-2(3H)-ones.
The important role of phospholipase A.sub.2 in mammalian metabolism through the formation of prostaglandins is now well known. See W. Vogt, Advances in Prostaglandins and Thromboxane Research, Vol. 3, page 89 (1978); P. C. Isakson, et al., Advances in Prostaglandin and Thromboxane Research, Vol. 3, page 113, (1978). Phospholipase A.sub.2 is responsible for the hydrolysis of arachidonic acid-containing phospholipids, thereby providing substrate for the multiple enzymes of the arachidonic acid cascade.
The products of the arachidonic acid cascade are varied. These products include prostaglandins, thromboxanes, leukotrienes, and other hydroxylated derivatives of arachidonic acid, which are referred to as "eicosanoids." While generally the products of the cascade are beneficial, in certain disease processes and other conditions the excessive production of eicosanoids induces deleterious consequences such as inflammation (see paper by N. A. Plummer, et al.; abstracted in Journal of Investigative Dermatology, Vol. 68, No. 4, p. 246 (1977)); erythema (N. A. Plummer, supra); platelet aggregation (B. B. Vargaftig, J. Pharm. Pharmacol., Vol. 29, p. 222-228 (1977)); and the release of SRS-A (slow reacting substance-anaphylaxis), a known mediator of allergenic responses. The inhibition of phospholipase A.sub.2 prevents these and similar conditions mediated by the action of this enzyme.
Some inhibitors of phospholipase A.sub.2 are known. R. J. Flower and G. J. Blackwell have shown that certain anti-inflammatory steroids induce biosynthesis of a phospholipase A.sub.2 inhibitor which prevents prostaglandin generation. See Nature, Vol. 278, p. 456 (1979). These steroids are not direct inhibitors of phospholipase A.sub.2, but rather stimulate the synthesis of a phospholipase inhibiting factor called lipocortin, lipomodulin, or macrocortin.
Some examples of direct phospholipase A.sub.2 inhibition are known. Indomethacin, a drug with anti-inflammatory properties, has been shown to inhibit at least one phospholipase A.sub.2 enzyme. See K. L. Kaplan, et al., Proc. Natl. Acad. Sci., Vol. 75, No. 6, pp. 2955-2988 (1978). The compound has been shown to inhibit phospholipase A.sub.2 enzymes, isolated respectively from the venoms of Russel Viper, Crotalus adamanteus, and bee, and from pig pancreas. Certain local anesthetics have been shown to inhibit phospholipase A.sub.2 activity by competing with calcium ion, which appears to be a requirement for phospholipase activity. See W. Vogt, Advances in Prostaglandin and Thromboxane Research, Vol. 3 p. 89 (1978). Bromphenacyl bromide has been shown to inhibit phospholipase A.sub.2 by acylating a histadine residue which is the active site of the molecule. See M. Roberts, et al., Journal of Biological Chemistry, Vol. 252, pp. 2405-2411 (1977). R. Blackwell, et al., in British Journal of Pharmacy, Vol. 62, p. 79-89 (1978) has disclosed that mepacrine inhibits the activity of phospholipase A.sub.2 derived from perfused guinea pig lung. Certain butyrophenones are disclosed as phospholipase A.sub.2 inhibitors in U.S. Pat. No. 4,239,780.